Conditioned fear and extinction learning performance and its association with psychiatric symptoms in active duty Marines

Abstract

Summary Background Posttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recent wars in Iraq and Afghanistan. Nevertheless, despite a sharp increase in the incidence of psychiatric disorders in returning veterans, empirically based prevention strategies are still lacking. To develop effective prevention and treatment strategies, it is necessary to understand the underlying biological mechanisms contributing to PTSD and other trauma related symptoms. Methods The “Marine Resiliency Study II” (MRS-II; October 2011–October 2013) Neurocognition project is an investigation of neurocognitive performance in Marines about to be deployed to Afghanistan. As part of this investigation, 1195 Marines and Navy corpsmen underwent a fear conditioning and extinction paradigm and psychiatric symptom assessment prior to deployment. The current study assesses (1) the effectiveness of the fear potentiated startle paradigm in producing fear learning and extinction and (2) the association of performance in the paradigm with baseline psychiatric symptom classes (healthy: n = 923, PTSD symptoms: n = 42, anxiety symptoms: n = 37, and depression symptoms: n = 12). Results Results suggest that the task was effective in producing differential fear learning and fear extinction in this cohort. Further, distinct patterns emerged differentiating the PTSD and anxiety symptom classes from both healthy and depression classes. During fear acquisition, the PTSD symptom group was the only group to show deficient discrimination between the conditioned stimulus (CS+) and safety cue (CS−), exhibiting larger startle responses during the safety cue compared to the healthy group. During extinction learning, the PTSD symptom group showed significantly less reduction in their CS+ responding over time compared to the healthy group, as well as reduced extinction of self-reported anxiety to the CS+ by the end of the extinction session. Conversely, the anxiety symptom group showed normal safety signal discrimination and extinction of conditioned fear, but exhibited increased baseline startle reactivity and potentiated startle to CS+, as well as higher self-reported anxiety to both cues. The depression symptom group showed similar physiological and self-report measures as the healthy group. Discussion These data are consistent with the idea that safety signal discrimination is a relatively specific marker of PTSD symptoms compared to general anxiety and depression symptoms. Further research is needed to determine if deficits in fear inhibition vs. exaggerated fear responding are separate biological “domains” across anxiety disorders that may predict differential biological mechanisms and possibly treatment needs. Future longitudinal analyses will examine whether poor learning of safety signals provides a marker of vulnerability to develop PTSD or is specific to symptom state.

On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development

“…These data are in line with findings that subjects with PTSD do not show physiological discrimination between CS+ and CS− cues, even though they report contingency awareness perfectly accurately (Acheson et al 2015b;Jovanovic et al 2012). This deficit in "automatic" fear discrimination between safe and threat cues appears to be specific to PTSD symptoms compared to generalized anxiety or depression symptoms (Acheson et al 2015b). Thus, pharmacological enhancement of cue discrimination may be an effective strategy for a number of anxiety disorders, not just PTSD.…”

“…Relative to healthy controls, PTSD patients as well as panic disorder and generalized anxiety disorder patients show shallow fear generalization gradients, indicating overgeneralization of conditioned fear (Lissek et al 2010(Lissek et al , 2014aLissek and van Meurs 2014). These data are in line with findings that subjects with PTSD do not show physiological discrimination between CS+ and CS− cues, even though they report contingency awareness perfectly accurately (Acheson et al 2015b;Jovanovic et al 2012). This deficit in "automatic" fear discrimination between safe and threat cues appears to be specific to PTSD symptoms compared to generalized anxiety or depression symptoms (Acheson et al 2015b).…”

“…As might be expected, increased fear-potentiated startle is associated with high levels of re-experiencing symptoms in PTSD patients ) and attentional bias to threat (Fani et al 2012). However, in a study that directly compared fear acquisition across subjects with PTSD, general anxiety, or depression symptoms, increased fear expression was significantly higher in individuals with general cognitive and somatic anxiety symptoms rather than PTSD or depression symptoms (Acheson et al 2015b). Greater conditioned fear expression has also been reported in other anxiety disorders, such as panic disorder (Grillon et al 2008) and bipolar disorder (Acheson et al 2015c).…”

“…In a recent comparative study across subjects reporting primarily PTSD, general anxiety, or depression symptoms, extinction deficits were only observed in subjects with PTSD (Acheson et al 2015b), suggesting that poor extinction is specifically related to trauma-related symptoms as opposed to general symptoms of low mood or ruminative anxiety. PTSD patients also exhibit functional and structural abnormalities in the fear extinction network including the hippocampus, amygdala, and frontal cortex [for review see Acheson et al (2012a), Shvil et al (2013)].…”

“…PTSD patients exhibit reduced fear extinction learning and retention in the laboratory, indicating that poor extinction of fear responses to trauma-related cues may be a mechanism underlying PTSD (Acheson et al 2015b;Milad et al 2008;Norrholm et al 2011). In a recent comparative study across subjects reporting primarily PTSD, general anxiety, or depression symptoms, extinction deficits were only observed in subjects with PTSD (Acheson et al 2015b), suggesting that poor extinction is specifically related to trauma-related symptoms as opposed to general symptoms of low mood or ruminative anxiety.…”